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WO1999055684A1 - Synthese sur support solide de 2-oxopiperazines sulfonees - Google Patents

Synthese sur support solide de 2-oxopiperazines sulfonees Download PDF

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Publication number
WO1999055684A1
WO1999055684A1 PCT/US1999/009091 US9909091W WO9955684A1 WO 1999055684 A1 WO1999055684 A1 WO 1999055684A1 US 9909091 W US9909091 W US 9909091W WO 9955684 A1 WO9955684 A1 WO 9955684A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
hydrogen
resin
ester
Prior art date
Application number
PCT/US1999/009091
Other languages
English (en)
Inventor
Adam Golebiowski
Sean Rees Klopfenstein
Original Assignee
The Procter & Gamble Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to EP99920061A priority Critical patent/EP1073644A1/fr
Priority to AU37643/99A priority patent/AU3764399A/en
Priority to JP2000545844A priority patent/JP2002513010A/ja
Priority to IL13912199A priority patent/IL139121A0/xx
Priority to CA002328934A priority patent/CA2328934A1/fr
Publication of WO1999055684A1 publication Critical patent/WO1999055684A1/fr
Priority to NO20005303A priority patent/NO20005303L/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the subject invention relates to methods for synthesizing sulfonated 2- oxopiperazine and homologous compounds, including libraries of such compounds, using a solid-support resin to facilitate purification of intermediates.
  • the subject invention involves processes for making sulfonated 2- oxopiperazine compounds:
  • the subject invention also includes the above processes where the above ⁇ - amino acid ester is replaced by a ⁇ -amino acid ester (or longer homologous ester) and/or the above ⁇ -amino alcohol is replaced by a ⁇ -amino alcohol (or longer homologous alcohol), such that the final products are the homologous 7-member or 8-member (or larger) ring compounds.
  • R 3 may also be attached to the N from the amino alcohol (eliminating the H attached thereto), thus resulting in a fused-ring product.
  • alkyl means a hydrocarbon chain which is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted.
  • alkyl may be used alone or as part of another word where it may be shortened to "alk” (e.g., in alkoxy, alkylacyl).
  • Preferred linear alkyl have from one to about twenty carbon atoms, more preferably from one to about six carbon atoms, more preferably still from one to about four carbon atoms; most preferred are methyl or ethyl.
  • Preferred cyclic and branched alkyl have from three to about twenty carbon atoms, more preferably from three to about six carbon atoms.
  • Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused hydrocarbon rings.
  • Preferred alkyl are unsaturated with from one to about three double or triple bonds; preferably they are mono- unsaturated with one double bond; more preferred alkyl are saturated.
  • substituents of alkyl include alkyl, aryl, aryloxy, alkoxy, alkyl or aryl ester. More preferred alkyl are unsubstituted.
  • heteroatom means a nitrogen, oxygen, or sulfur atom.
  • alkylene means a linear alkyl which is attached to other moieties both ends of the alkylene
  • heteroalkylene means an alkylene having one or more heteroatoms between carbons or/and at one or both ends of the alkylene.
  • aryl means an aromatic hydrocarbon ring which is substituted or unsubstituted.
  • aryl may be used alone or as part of another word (e.g., in aryloxy, arylacyl).
  • Preferred aryl have from six to about ten carbon atoms in the aromatic ring(s), and a total of from about six to about twenty, preferably to about twelve, carbon atoms.
  • Preferred aryl is phenyl or naphthyl; most preferred is phenyl.
  • Preferred substituents of aryl include alkyl, aryl, alkoxy, aryloxy, alkyl or aryl ester, halo, nitro, amino, cyano, acyl, alkyl- or arylacyl. More preferred aryl are unsubstituted.
  • heterocycle means a cyclic hydrocarbon chain with one or more heteroatoms in the hydrocarbon ring(s).
  • the ring(s) may be saturated, unsaturated, or aromatic.
  • Preferred heterocycles have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms, most preferably one heteroatom.
  • Preferred heterocycles have from three to about twelve carbon plus heteroatoms in the ring(s), more preferably from three to about seven; and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten.
  • Preferred heterocycles have one ring, but may have two, three, or more, fused rings. Heterocycles are unsubstituted or substituted. Preferred heterocycle substituents are the same as for alkyl.
  • heteroaryl means an aromatic heterocycle.
  • Preferred heteroaryls have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms, most preferably one heteroatom.
  • Preferred heteroaryls have from five to about twelve carbon plus heteroatoms in the aromatic ring(s), more preferably from five to about nine; and a total of from five to about twenty carbon plus heteroatoms, more preferably from 5
  • heteroaryls have one ring, but may have two or more fused rings, at least one of which contains at least one ring heteroatom. Heteroaryls are unsubstituted or substituted. Preferred heteroaryl substituents are the same as for aryl.
  • the subject invention processes use solid-support resins capable of linking with the carboxy moiety of amino acids.
  • Preferred resins for use in the subject processes have hydroxyalkylene linking moieties.
  • Particularly preferred are Merrifield or Wang resins such as polystyrene based resin Merrifield (100-200 mesh), 2%DVB - catalog number 01-64-0104, available from Calbiochem- Novabiochem Corp., San Diego, California, a hydroxymethylpolystyrene resin.
  • N-protected amino acids can be readily esterified to the above-mentioned resins.
  • resins are commercially available with N-protected amino acids already esterified to the resin (e.g. Boc-Gly-Merrifield resin catalog number 04-12-2507, available from Calbiochem-Novabiochem Corp.).
  • N-protecting groups on the above-mentioned amino acids are well known; they include t-butyloxycarbonyl (Boc) and 9-fiuorenylmethoxycarbonyl (Fmoc); most preferred is Boc.
  • Boc t-butyloxycarbonyl
  • Fmoc 9-fiuorenylmethoxycarbonyl
  • a subject invention process involves starting with a N-protected amino acid ester of a solid-support resin:
  • the N-protecting group is generally present on amino acid esters of resins because it is needed to properly esterify the amino acid onto the resin.
  • the subject process first requires removing this N-protecting group; this can be accomplished using any known method. (If the N-protecting group is not present, this procedure can be skipped.)
  • This reaction is preferably carried out under basic conditions (e.g. diisopropylethyl amine) in a halogenated solvent (e.g. dichloromethane).
  • basic conditions e.g. diisopropylethyl amine
  • a halogenated solvent e.g. dichloromethane
  • R! can be any moiety that provides stable intermediates and final products for the subject processes.
  • Preferred R ⁇ include hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester. More preferred R!
  • R* are hydrogen and alkyl having from one to about four carbon atoms, the alkyl preferably being saturated, linear or branched, unsubstituted or substituted with one or more, preferably one, moiety selected from hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanido, carboxy, carbamoyl, phenyl, hydroxyphenyl, indole, and imidazo. Still more preferred R* are the side chains of the natural amino acids.
  • R 2 can be any moiety that provides stable intermediates and final products for the subject processes.
  • Preferred R 2 include hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl ester ; more preferred R2 are aryl and heterocycle.
  • n is an integer from 0 to about 5, preferably from 0 to about 3; more preferably n is 0 or 1 , most preferably 0.
  • the next step of a subject invention involves a Mitsunobu reaction of 3 with a N-protected amino alcohol:
  • Mitsunobu reactions are disclosed in a) Hughes, D., " The Mitsunobu Reaction", Organic Reactions, vol. 42, Paquette, L.A., ed.; 1992, John Wiley & Sons, NY, pp. 335-656; b) Swayze, E. E., Tetrahedron Lett., vol.38 (1997), p. 8643.
  • R 3 can be any moiety that provides stable intermediates and final products for the subject processes.
  • Preferred R 3 include hydrogen, alkyl, aryl, heterocycle, heteroaryl, alkyl or aryl amine, alkyl or aryl acyl, alkyl or aryl ester, alkyl or aryl sulfonyl.
  • R- 3 are hydrogen and alkyl having from one to about four carbon atoms, the alkyl preferably being saturated, linear or branched, unsubstituted or substituted with one or more, preferably one, moiety selected from hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, guanido, carboxy, 8
  • R- 3 are the side chains of the natural amino acids.
  • R ⁇ is an alkylene or heteroalkylene moiety.
  • R ⁇ has from
  • R4 is saturated and unsubstituted or substituted with one moiety selected from hydroxy, methoxy, ethoxy, thio, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, and carbamoyl. Most preferred R4 is n-propylene.
  • m is an integer from 1 to 5, preferably from 1 to 3; more preferably m is 1 or 2, most preferably 1.
  • the next step of a subject invention process involves removing the N- protecting group from 5 or 8 by any known method (similar to the analogous procedure above).
  • the next step of a subject invention process involves cyclizing the product: O
  • This cyclizing/cleavage from resin reaction is carried out in acidic conditions in a mildly polar solvent at an elevated temperature.
  • Cleavage and cyclization is preferably achieved in a solution of acetic acid in 2-butanol.
  • the cleavage and cyclization reaction is not highly dependent on the amino acid or amino aldehyde used.
  • the temperature required for maximum cleavage and cyclization is typically from about 25 °C to about 70°C.
  • libraries of compounds of structure 6 and/or 9 can readily be carried out using a multiple cell procedure, e.g., 96 plate format (e.g., Robbins Block), where different compounds having different combinations of Rl, R2 and R 3 or R ⁇ can be made in each cell simultaneously. Also, libraries of mixtures of compounds of structure 6 and/or 9 can be made by reacting reagents which are mixtures rather than single compounds. Both types of libraries are useful for rapid screening of numerous compounds for pharmacological and other activities.
  • 96 plate format e.g., Robbins Block
  • a Boc-amino acid attached via an ester link to Merrifield resin 10 is used as starting material.
  • the amino group is deprotected and sulfonamide H is formed.
  • the resin is washed with dilute acetic acid in order to remove any residual amine.
  • Mitsunobu reaction with Boc-proctected amino alcohol 12 leads to alkylated product 13. To ensure the completion of this process, alkylation is 10
  • Boc-Ala-Merrifield resin ester (1.070 g, 0.74 mmol, 0.69 mmol/g, NovaBiochem) is rinsed several times with dichloromethane (DCM). It is then treated with trifluoroacetic acid (95%; TFA/H2O) for 1 h at room temperature. The resin is washed with DCM several times, then with 5% diisopropylethylamine (DIPEA) in DCM, and again with DCM. The suspended resin (DCM ca.
  • Resin ester 15 (200 mg, 0.122 mmol, 0.61 mmol/g) is rinsed several times with tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • Triphenylphosphine (PI13P) (0.37 mmol, 97 mg, 3 eq)
  • S)-l-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (N-Boc-L-prolinol) (0.37 mmol, 75 mg, 3 eq) are dissolved in THF (ca. 4 mL) and added to the reactor, followed by diisopropyl azodicarboxylate (DIAD) (0.37 mmol, 75 mg, 73 ⁇ L, 3 eq).
  • DIAD diisopropyl azodicarboxylate
  • Compound 17 is prepared using a similar process.
  • Resin ester 15 300 mg, 0.183 mmol, 0.61 mmol/g is rinsed several times with tetrahydrofuran (THF).
  • Triphenylphosphine (PI13P) (0.56 mmol, 148 mg, 3 eq)
  • N-Boc-L-alaninol (0.56 mmol, 113 mg, 3 eq) are dissolved in THF (ca. 9 mL) and added to the reactor, followed by diisopropyl azodicarboxylate (DIAD) (0.56 mmol, 113 mg, 110 ⁇ L, 3 eq).
  • THF tetrahydrofuran
  • DIAD diisopropyl azodicarboxylate
  • the reaction mixture is vigorously shaken for 8 h and filtered.
  • the resin is washed several times with THF.
  • the alkylation procedure is repeated one more time.
  • the crude resin product from the previous step is rinsed several times with DCM and then treated with trifluoroacetic acid (95%; TFA/H2O) for 1 h at room temperature.
  • the resin is washed with DCM and methanol and finally suspended in 2M AcOH/2-BuOH and vigorously shaken at 70°C for 48 h and filtered.
  • the resin is washed a few more times with DCM and methanol; filtrates are collected and evaporated.
  • the oily residue is co-evaporated with chloroform (in order to remove traces of acetic acid and butanol) to give a purified product of 17: 12

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne des procédés qui permettent de fabriquer des composés de 2-oxopipérazine et homologues au moyen d'un résine support solide et qui consistent à: (a) retirer le groupe protecteur de l'ester d'aminoacide protégé N (le cas échéant), (b) faire réagir la résine non protégée qui en résulte avec un chlorure de sulfuryle, (c) faire réagir le produit intermédiaire avec un alcool amino N-protégé, (d) retirer le groupe de protection-N de N de l'alcool amino et (e) séparer le produit de la résine.
PCT/US1999/009091 1998-04-29 1999-04-27 Synthese sur support solide de 2-oxopiperazines sulfonees WO1999055684A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP99920061A EP1073644A1 (fr) 1998-04-29 1999-04-27 Synthese sur support solide de 2-oxopiperazines sulfonees
AU37643/99A AU3764399A (en) 1998-04-29 1999-04-27 Solid supported synthesis of sulfonated 2-oxopiperazines
JP2000545844A JP2002513010A (ja) 1998-04-29 1999-04-27 スルホン化２−オキソピペラジンの固体支持合成
IL13912199A IL139121A0 (en) 1998-04-29 1999-04-27 Solid supported synthesis of sulfonated 2-oxopiperazines
CA002328934A CA2328934A1 (fr) 1998-04-29 1999-04-27 Synthese sur support solide de 2-oxopiperazines sulfonees
NO20005303A NO20005303L (no) 1998-04-29 2000-10-20 Fastfase syntese av sulfonerte 2-oksopiperaziner

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8346898P 1998-04-29 1998-04-29
US60/083,468 1998-04-29

Publications (1)

Publication Number Publication Date
WO1999055684A1 true WO1999055684A1 (fr) 1999-11-04

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/009091 WO1999055684A1 (fr) 1998-04-29 1999-04-27 Synthese sur support solide de 2-oxopiperazines sulfonees

Country Status (7)

Country Link
EP (1) EP1073644A1 (fr)
JP (1) JP2002513010A (fr)
AU (1) AU3764399A (fr)
CA (1) CA2328934A1 (fr)
IL (1) IL139121A0 (fr)
NO (1) NO20005303L (fr)
WO (1) WO1999055684A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7964181B2 (en) 2006-03-30 2011-06-21 Palatin Technologies, Inc. Amino acid surrogates for peptidic constructs
US8114844B2 (en) 2006-03-30 2012-02-14 Palatin Technologies, Inc. Linear and cyclic melanocortin receptor-specific peptidomimetics

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010222A1 (fr) * 1995-09-13 1997-03-20 Cortech, Inc. Procede de preparation de piperazines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010222A1 (fr) * 1995-09-13 1997-03-20 Cortech, Inc. Procede de preparation de piperazines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHRIST. W. GROTE: "STEREOCONTROLLED SYNTHESIS OF DTPA ANALOGUES", JOURNAL OF ORGANIC CHEMISTRY., vol. 60, no. 21, 1995, AMERICAN CHEMICAL SOCIETY. EASTON., US, pages 6987 - 6997, XP002111365, ISSN: 0022-3263 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7964181B2 (en) 2006-03-30 2011-06-21 Palatin Technologies, Inc. Amino acid surrogates for peptidic constructs
US8114844B2 (en) 2006-03-30 2012-02-14 Palatin Technologies, Inc. Linear and cyclic melanocortin receptor-specific peptidomimetics

Also Published As

Publication number Publication date
CA2328934A1 (fr) 1999-11-04
NO20005303D0 (no) 2000-10-20
JP2002513010A (ja) 2002-05-08
NO20005303L (no) 2000-12-20
IL139121A0 (en) 2001-11-25
EP1073644A1 (fr) 2001-02-07
AU3764399A (en) 1999-11-16

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